Pharmaceutical composition and method for treating a joint-capsule arthropathy

Abstract

A pharmaceutical composition for use in treating a joint-capsule arthropathy comprising an effective amount of one or more of a locally administered, optionally encapsulated therapeutic agent in admixture with a hyaluronic acid delivery vehicle and a method for use thereof in treating a joint-capsule arthropathy by intra-articular injection.

1 . A pharmaceutical composition for use in treating a joint-capsule arthropathy in a subject in need thereof comprising an effective amount of one or more of a locally administered, optionally encapsulated therapeutic agent in admixture with a hyaluronic acid delivery vehicle.  
   
   
       2 . The composition of  claim 1 , wherein the joint-capsule arthropathy is selected from osteoarthritis, joint-capsule injuries which have triggered or will trigger a pro-inflammatory response or arthropathies which have triggered or will trigger a pro-inflammatory response.  
   
   
       3 . The composition of  claim 2 , wherein the joint-capsule arthropathy is selected from a symptomatic range of arthropathies that are just beginning to develop, wherein bone degeneration and the level of pain experienced by the subject is at a minimum to those arthropathies wherein bone degeneration and the level of pain experienced by the subject requires surgical intervention or where the administration of one or more of a therapeutic agent for pain intervention has led to a decreased quality of life.  
   
   
       4 . The composition of  claim 3 , wherein joint-capsule injuries are the result of an endogenous or exogenous source of insult.  
   
   
       5 . The composition of  claim 4 , wherein the endogenous source of insult is a genetic joint-disorder, abnormal bone growth, aggregation or cyst formation in a joint space, joint fusion, joint misalignment, compensation for joint misalignment or other types of musculo-skeletal injuries in other parts of the body or injuries resulting from wear, repetitive motion or immobility.  
   
   
       6 . The composition of  claim 4 , wherein the exogenous source of insult is a musculo-skeletal injury caused by trauma, a sport-related injury or immobility.  
   
   
       7 . The composition of  claim 1 , wherein at least one therapeutic agent is encapsulated.  
   
   
       8 . The composition of  claim 1 , further comprising one or more of an encapsulated therapeutic agent and one or more of an additional, different optionally encapsulated therapeutic agent.  
   
   
       9 . The composition of  claim 1 , further comprising one or more of an encapsulated therapeutic agent and one or more of an additional, different unencapsulated therapeutic agent.  
   
   
       10 . The composition of  claim 1 , further comprising two or more of an encapsulated therapeutic agent, wherein each encapsulated agent has a dissimilar release profile.  
   
   
       11 . The composition of  claim 1 , further comprising two or more of an encapsulated therapeutic agent, each having a dissimilar release profile, and one or more of an optionally encapsulated therapeutic agent.  
   
   
       12 . The composition of  claim 1 , wherein the therapeutic agent is selected from a non-steroidal anti-inflammatory drug, a nitric oxide inhibitor, a cyclooxygenase inhibitor, a prostaglandin inhibitor, an interleukin inhibitor, a leukotriene inhibitor, an inflammatory or growth proliferation kinase inhibitor, an inflammatory cytokine inhibitor, a corticosteroid, a hyaluronidase enzyme inhibitor, a matrix metalloproteinase inhibitor, an aggrecanase inhibitor, an apoptosis inhibitor, a cartilage enhancing factor or a bone morphogenic protein.  
   
   
       13 . The composition of  claim 12 , wherein the non-steroidal anti-inflammatory drug is selected from analogs of carboxylic acid, acetic acid, propionic acid, salicylic acid, hydratropic acid, hydroxamic acid, benzoic/xylylanthranilic acid, benzene acetic acid, indole acetic acid, indene acetic acid, toluoylpyrrole acetic acid, naphthalene acetic acid, benzopyranopyridine acetic acid, pyrazolidinedione or benzthiazine and the like or a salt or ester form or mixture thereof.  
   
   
       14 . The composition of  claim 12 , wherein the non-steroidal anti-inflammatory drug is selected from suprofen, tepoxalin, mefenamic acid, ibuprofen, diclofenac, alclofenac, indomethacin, sulindac, tolmetin, naproxen, pranoprofen, phenylbutazone, oxyphenbutazone or piroxicam and the like or a salt or ester form or mixture thereof.  
   
   
       15 . The composition of  claim 14 , wherein the non-steroidal anti-inflammatory drug is selected from suprofen, tepoxalin, ibuprofen, diclofenac, indomethacin, sulindac, tolmetin, naproxen or oxyphenbutazone and the like or a salt or ester form or mixture thereof.  
   
   
       16 . The composition of  claim 15 , wherein the non-steroidal anti-inflammatory drug is selected from suprofen, tepoxalin or tolmetin and the like or a salt or ester form or mixture thereof.  
   
   
       17 . The composition of  claim 12 , wherein the therapeutic agent is at least one non-steroidal anti-inflammatory drug which is a cyclooxygenase, leukotriene or prostaglandin inhibitor.  
   
   
       18 . The composition of  claim 17 , wherein the cyclooxygenase inhibitor is a 5LO-1, COX-1 or COX-2 inhibitor.  
   
   
       19 . The composition of  claim 17 , wherein the leukotriene inhibitor is a LTB 4  inhibitor.  
   
   
       20 . The composition of  claim 17 , wherein the prostaglandin inhibitor is a PGE 2  inhibitor.  
   
   
       21 . The composition of  claim 13 , wherein the non-steroidal anti-inflammatory drug is a 5LO-1, COX-1, COX-2, LTB 4  or TXB 2  inhibitor.  
   
   
       22 . The composition of  claim 21 , wherein the 5LO-1 inhibitor is an inhibitor having an IC 50  of from about 0.010 μM to about 10 μM.  
   
   
       23 . The composition of  claim 21 , wherein the COX-1 inhibitor is an inhibitor having an IC 50  of from about 0.06 μM to about 12 μM.  
   
   
       24 . The composition of  claim 21 , wherein the COX-2 inhibitor is an inhibitor having an IC 50  of from about 0.05 μM to about 6 μM.  
   
   
       25 . The composition of  claim 21 , wherein the LTB 4  inhibitor is an inhibitor having an IC 50  of from about 0.035 μM to about 2 μM.  
   
   
       26 . The composition of  claim 21 , wherein the TXB 2  inhibitor is an inhibitor having an IC 50  of from about 0.002 μM to about 0.04 μM.  
   
   
       27 . The composition of  claim 12 , wherein the inflammatory kinase inhibitor is a MAP kinase inhibitor or isoform thereof.  
   
   
       28 . The composition of  claim 27 , wherein the MAP kinase inhibitor is a p38, ERK or JNK2 kinase inhibitor or isoform thereof.  
   
   
       29 . The composition of  claim 28 , wherein the isoform of the p38 MAP kinase inhibitor is a selective p38α MAP kinase inhibitor.  
   
   
       30 . The composition of  claim 12 , wherein the growth proliferation kinase inhibitor is sirolimus.  
   
   
       31 . The composition of  claim 12 , wherein the inflammatory cytokine inhibitor is selected from a TNF-α inhibitor, an IL-1α inhibitor, IL-1β inhibitor, IL-6 inhibitor, IL-10 inhibitor, IL-12 inhibitor or an IL-17 inhibitor.  
   
   
       32 . The composition of  claim 31 , wherein the inflammatory cytokine inhibitor is selected from a TNF-α inhibitor, an IL-1α inhibitor, IL-1β inhibitor, IL-6 inhibitor or IL-10 inhibitor.  
   
   
       33 . The composition of  claim 1 , wherein the therapeutic agent is one or more of a non-steroidal anti-inflammatory drug selected from  claim 13 .  
   
   
       34 . The composition of  claim 1 , wherein the therapeutic agent is one or more of a non-steroidal anti-inflammatory drug selected from  claim 13  in combination with one or more of an additional, different therapeutic agent selected from  claim 12 .  
   
   
       35 . The composition of  claim 1 , wherein the composition further comprises a combination product having two or more of a therapeutic agent selected from  claim 12 .  
   
   
       36 . The composition of  claim 35 , wherein the combination product further comprises one or more of a therapeutic agent selected from  claim 12  and at least one additional, different therapeutic agent selected from  claim 12 .  
   
   
       37 . The composition of  claim 35 , wherein the combination product further comprises a mixture of two or more of a therapeutic agent selected from  claim 12  for use in treating a joint-capsule arthropathy, wherein the combination product achieves pain relief, modification of the arthropathy and its progression or delay of surgical intervention.  
   
   
       38 . The composition of  claim 1 , wherein the therapeutic agent further comprises a pharmaceutically acceptable salt, pro-drug or pharmaceutically active metabolite of a therapeutic agent selected from  claim 12 .  
   
   
       39 . The composition of  claim 1 , wherein the therapeutic agent is present in a particle form, wherein the particle form is selected from a finely-divided particle, wherein the particle size is in a range of from about 0.5 microns to about 200 microns.  
   
   
       40 . The composition of  claim 39 , wherein the particle size is in a range of from about 5 microns to about 50 microns.  
   
   
       41 . The composition of  claim 39 , wherein the mean particle size is in a range of from about 25 microns to about 50 microns.  
   
   
       42 . The composition of  claim 1 , wherein the therapeutic agent is dissolved, suspended or otherwise dispersed in the hyaluronic acid delivery vehicle.  
   
   
       43 . The composition of  claim 42 , wherein the therapeutic agent is suspended in a natural or synthetic biodegradable polymer or copolymer or mixture thereof or adsorbed in a carrier matrix.  
   
   
       44 . The composition of  claim 1 , wherein the encapsulated form of the therapeutic agent is a microparticle form selected from a microsphere, a micropellet, a nanoparticle, or a liposome.  
   
   
       45 . The composition of  claim 44 , wherein the microparticle form is prepared by the steps of 
 (a) dissolving or dispersing one or more of a therapeutic agent, a biodegradable polymer or a blend thereof and other optional ingredients in an organic solvent or cosolvent to form an organic phase;    (b) mixing the organic phase from step (a) with an aqueous phase to form an emulsion; (c) extracting the emulsion from step (b) into a larger volume of the organic phase solvent to thus form at least one microparticle; and    (d) recovering the microparticle from step (c) using a filtration or centrifugation means and optionally washing the recovered microparticles.    
   
   
       46 . The composition of  claim 1 , wherein the therapeutic agent is selected from a finely-divided uncoated particle, a particle coated with a biodegradable polymer or a blend thereof or a particle coated with a biodegradable polymer or a blend thereof as a first layer and then with a plurality of biodegradable polymer layers or a blend thereof.  
   
   
       47 . The composition of  claim 46 , wherein the polymer or copolymer or blend thereof is selected from PLA, PGA, PLGA or PLA-PLGA or a blend thereof.  
   
   
       48 . The composition of  claim 38 , wherein the carrier matrix is hyaluronic acid.  
   
   
       49 . The composition of  claim 1 , wherein the hyaluronic acid delivery vehicle is a purified form of hyaluronic acid or a salt form thereof.  
   
   
       50 . The composition of  claim 49 , wherein the hyaluronic acid salt form is a sodium salt, potassium salt, ammonium salt or a C (1-5) alkyl amine salt thereof.  
   
   
       51 . The composition of  claim 49 , wherein the purified salt form of hyaluronic acid is sodium hyaluronate.  
   
   
       52 . The composition of  claim 49 , wherein the hyaluronic acid has a Molecular Weight of from about 0.5 to about 6.0×10 6  Daltons and is present at a concentration of from about 0.5% w/v to about 2% w/v.  
   
   
       53 . The composition of  claim 49 , wherein the hyaluronic acid is present at a concentration in a range of from about 1% w/v to about 2% w/v.  
   
   
       54 . The composition of  claim 1 , wherein the hyaluronic acid delivery vehicle has a pH of from about 6.0 to about 7.0.  
   
   
       55 . The composition of  claim 1 , wherein the hyaluronic acid delivery vehicle has an osmotic pressure ratio of from about 0.8 to about 1.2 as compared to an isotonic saline solution of from about 0.8% to about 0.9%.  
   
   
       56 . The composition of  claim 1 , wherein the hyaluronic acid delivery vehicle has a viscosity in the range of from about 500 cps to about 2000 cps at a temperature of about 300° C.  
   
   
       57 . The composition of  claim 1 , wherein the therapeutic agent is an optionally encapsulated non-steroidal anti-inflammatory drug selected from suprofen, tepoxalin or tolmetin or a mixture thereof.  
   
   
       58 . The composition of  claim 1 , wherein the therapeutic agent is an optionally encapsulated inflammatory kinase inhibitor selected from a p38 MAP kinase inhibitor or an isoform thereof.  
   
   
       59 . The composition of  claim 1 , wherein the therapeutic agent is an optionally encapsulated growth proliferation kinase inhibitor selected from sirolimus.  
   
   
       60 . The composition of  claim 1 , wherein the therapeutic agent is an optionally encapsulated inflammatory cytokine inhibitor selected from a TNF-α inhibitor, an IL-1α inhibitor, IL-1βinhibitor, IL-6 inhibitor, IL-10 inhibitor, IL-12 inhibitor or an IL-17 inhibitor.  
   
   
       61 . The composition of  claim 1 , wherein the therapeutic agent is an optionally encapsulated inflammatory cytokine inhibitor selected from a TNF-α inhibitor, an IL-1α inhibitor, IL-1β inhibitor, IL-6 inhibitor or IL-10 inhibitor.  
   
   
       62 . The composition of  claim 1 , wherein the effective amount of an unencapsulated therapeutic agent is from about 0.0001 mg/injection to about 300 mg/injection.  
   
   
       63 . The composition of  claim 1 , wherein the effective amount of an encapsulated therapeutic agent is from about 0.0001 mg/injection to about 300 mg/injection.  
   
   
       64 . A method for treating a joint-capsule arthropathy in a subject in need thereof comprising locally administering to the subject an effective amount of a pharmaceutical composition comprising an effective amount of an optionally encapsulated therapeutic agent in admixture with a hyaluronic acid delivery vehicle.  
   
   
       65 . The method of  claim 64 , wherein the joint-capsule arthropathy is selected from osteoarthritis, joint-capsule injuries which have triggered or will trigger a pro-inflammatory response or arthropathies which have triggered or will trigger a pro-inflammatory response.  
   
   
       66 . The method of  claim 65 , wherein the joint-capsule arthropathy is selected from a symptomatic range of arthropathies that are just beginning to develop, wherein bone degeneration and the level of pain experienced by the subject is at a minimum to those arthropathies wherein bone degeneration and the level of pain experienced by the subject requires surgical intervention or where the administration of one or more of a therapeutic agent for pain intervention has led to a decreased quality of life.  
   
   
       67 . The method of  claim 66 , wherein joint-capsule injuries are the result of an endogenous or exogenous source of insult.  
   
   
       68 . The method of  claim 67 , wherein the endogenous source of insult is a genetic joint-disorder, abnormal bone growth, aggregation or cyst formation in a joint space, joint fusion, joint misalignment, compensation for joint misalignment or other types of musculo-skeletal injuries in other parts of the body or injuries resulting from wear, repetitive motion or immobility.  
   
   
       69 . The method of  claim 67 , wherein the exogenous source of insult is a musculo-skeletal injury caused by trauma, a sport-related injury or immobility.  
   
   
       70 . The method of  claim 64 , wherein the therapeutic agent is selected from a non-steroidal anti-inflammatory drug, a nitric oxide inhibitor, a cyclooxygenase inhibitor, a prostaglandin inhibitor, an interleukin inhibitor, a leukotriene inhibitor, an inflammatory or growth proliferation kinase inhibitor, an inflammatory cytokine inhibitor, a corticosteroid, a hyaluronidase enzyme inhibitor, a matrix metalloproteinase inhibitor, an aggrecanase inhibitor, an apoptosis inhibitor, a cartilage enhancing factor or a bone morphogenic protein.  
   
   
       71 . The method of  claim 70 , wherein the non-steroidal anti-inflammatory drug is selected from analogs of carboxylic acid, acetic acid, propionic acid, salicylic acid, hydratropic acid, hydroxamic acid, benzoic/xylylanthranilic acid, benzene acetic acid, indole acetic acid, indene acetic acid, toluoylpyrrole acetic acid, naphthalene acetic acid, benzopyranopyridine acetic acid, pyrazolidinedione or benzthiazine and the like or a salt or ester form or mixture thereof.  
   
   
       72 . The method of  claim 71 , wherein the non-steroidal anti-inflammatory drug is selected from suprofen, tepoxalin, mefenamic acid, ibuprofen, diclofenac, alclofenac, indomethacin, sulindac, tolmetin, naproxen, pranoprofen, phenylbutazone, oxyphenbutazone or piroxicam and the like or a salt or ester form or mixture thereof.  
   
   
       73 . The method of  claim 72 , wherein the non-steroidal anti-inflammatory drug is selected from suprofen, tepoxalin, ibuprofen, diclofenac, indomethacin, sulindac, tolmetin, naproxen or oxyphenbutazone and the like or a salt or ester form or mixture thereof.  
   
   
       74 . The method of  claim 73 , wherein the non-steroidal anti-inflammatory drug is selected from suprofen, tepoxalin or tolmetin and the like or a salt or ester form or mixture thereof.  
   
   
       75 . The method of  claim 64 , wherein the therapeutic agent is at least one non-steroidal anti-inflammatory drug which is a cyclooxygenase, leukotriene or prostaglandin inhibitor.  
   
   
       76 . The method of  claim 75 , wherein the cyclooxygenase inhibitor is a 5LO-1, COX-1 or COX-2 inhibitor.  
   
   
       77 . The method of  claim 75 , wherein the leukotriene inhibitor is a LTB 4  inhibitor.  
   
   
       78 . The method of  claim 75 , wherein the prostaglandin inhibitor is a PGE 2  inhibitor.  
   
   
       79 . The method of  claim 71 , wherein the non-steroidal anti-inflammatory drug is a 5LO-1, COX-1, COX-2, LTB 4  or TXB 2  inhibitor.  
   
   
       80 . The method of  claim 79 , wherein the 5LO-1 inhibitor is an inhibitor having an IC 50  of from about 0.010 μM to about 10 μM.  
   
   
       81 . The method of  claim 79 , wherein the COX-1 inhibitor is an inhibitor having an IC 50  of from about 0.06 μM to about 12 μM.  
   
   
       82 . The method of  claim 79 , wherein the COX-2 inhibitor is an inhibitor having an IC 50  of from about 0.05 μM to about 6 μM.  
   
   
       83 . The method of  claim 79 , wherein the LTB 4  inhibitor is an inhibitor having an IC 50  of from about 0.035 μM to about 2 μM.  
   
   
       84 . The method of  claim 79 , wherein the TXB 2  inhibitor is an inhibitor having an IC 50  of from about 0.002 μM to about 0.04 μM.  
   
   
       85 . The method of  claim 70 , wherein the inflammatory kinase inhibitor is a MAP kinase inhibitor or isoform thereof.  
   
   
       86 . The method of  claim 85 , wherein the MAP kinase inhibitor is a p38, ERK or JNK2 kinase inhibitor or isoform thereof.  
   
   
       87 . The composition of  claim 86 , wherein the isoform of the p38 MAP kinase inhibitor is a selective p38α MAP kinase inhibitor.  
   
   
       88 . The method of  claim 70 , wherein the growth proliferation kinase inhibitor is sirolimus.  
   
   
       89 . The method of  claim 70 , wherein the inflammatory cytokine inhibitor is selected from a TNF-α inhibitor, an IL-1α inhibitor, IL-1β inhibitor, IL-6 inhibitor, IL-10 inhibitor, IL-12 inhibitor or an IL-17 inhibitor.  
   
   
       90 . The method of  claim 89 , wherein the inflammatory cytokine inhibitor is selected from a TNF-α inhibitor, an IL-1α inhibitor, IL-1β inhibitor, IL-6 inhibitor or IL-10 inhibitor.  
   
   
       91 . The method of  claim 64 , wherein the therapeutic agent is one or more of a non-steroidal anti-inflammatory drug selected from  claim 71 .  
   
   
       92 . The method of  claim 64 , wherein the therapeutic agent is one or more of a non-steroidal anti-inflammatory drug selected from  claim 71  in combination with one or more of an additional, different therapeutic agent selected from  claim 70 .  
   
   
       93 . The method of  claim 64 , wherein the composition further comprises a combination product having two or more of a therapeutic agent selected from  claim 70 .  
   
   
       94 . The method of  claim 93 , wherein the combination product further comprises one or more of a therapeutic agent selected from  claim 70  and at least one additional, different therapeutic agent selected from  claim 70 .  
   
   
       95 . The method of  claim 64 , wherein the combination product further comprises a mixture of two or more of a therapeutic agent selected from  claim 70  for use in treating a joint-capsule arthropathy, wherein the combination product achieves pain relief, modification of the arthropathy and its progression or delay of surgical intervention.  
   
   
       96 . The method of  claim 64 , wherein the composition further comprises a pharmaceutically acceptable salt, pro-drug or pharmaceutically active metabolite of a therapeutic agent selected from  claim 70  in admixture with a pharmaceutically acceptable carrier.  
   
   
       97 . The method of  claim 64 , wherein the therapeutic agent is present in a particle form, wherein the particle form is selected from a finely-divided particle, wherein the particle size is in a range of from about 0.5 microns to about 200 microns.  
   
   
       98 . The method of  claim 97 , wherein the particle size is in a range of from about 5 microns to about 50 microns.  
   
   
       99 . The method of  claim 97 , wherein the mean particle size is in a range of from about 25 microns to about 50 microns.  
   
   
       100 . The method of  claim 64 , wherein the therapeutic agent is dissolved, suspended or otherwise dispersed in the hyaluronic acid delivery vehicle.  
   
   
       101 . The method of  claim 64 , wherein the therapeutic agent is suspended in a natural or synthetic biodegradable polymer or copolymer or mixture thereof or adsorbed in a carrier matrix.  
   
   
       102 . The method of  claim 64 , wherein the encapsulated form of the therapeutic agent is a microparticle form selected from a microsphere, a micropellet, a nanoparticle, or a liposome.  
   
   
       103 . The method of  claim 64 , wherein the effective amount is a non-systemic, therapeutically effective amount.  
   
   
       104 . The method of  claim 64 , wherein the effective amount is in a range of from about 0.0001 mg/injection to about 300 mg/injection.  
   
   
       105 . The method of  claim 64 , wherein the method of locally administering further comprises transcapsular or transdiscal administration.  
   
   
       106 . The method of  claim 64 , wherein the joint capsule having an arthropathy is selected from a joint capsule having symptoms of periodic inflammation or a joint capsule having symptoms of chronic inflammation.  
   
   
       107 . The method of  claim 64 , wherein the method further comprises a non-systemic, therapeutically effective amount of a combination product for use in treating, ameliorating or preventing the development and progression of a joint-capsule arthropathy.  
   
   
       108 . The method of  claim 107 , wherein the combination product comprises a combination selected from one or more of an optionally encapsulated therapeutic agent or one or more of an encapsulated therapeutic agent or a combination of two one or more an encapsulated therapeutic agent and one or more of an additional, different optionally encapsulated therapeutic agent, wherein one or more of the therapeutic agent is each selected from  claim 70.